Computer Aided Drug Design (CADD): From Ligand-Based Methods to Structure-Based Approaches

324 Pages·2022·12.574 MB·English

by  Mithun Rudrapal, Chukwuebuka Egbuna

Computer Aided Drug Design (CADD):
From Ligand-Based Methods
to Structure-Based Approaches
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Computer Aided Drug
Design (CADD): From
Ligand-Based Methods
to Structure-Based
Approaches
Edited by
Mithun Rudrapal
DepartmentofPharmaceuticalChemistry,RasiklalM.DhariwalInstituteof
Pharmaceutical Education and Research,Pune,Maharashtra, India
Chukwuebuka Egbuna
NutritionalBiochemistryUnit,AfricaCentreofExcellenceinPublicHealth
and ToxicologicalResearch (ACE-PUTOR),University ofPort-Harcourt,
Port Harcourt,Rivers State; Department ofBiochemistry, Chukwuemeka
Odumegwu Ojukwu University, Uli, Anambra,Nigeria
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Contents
Contributors xi
1. Introduction to drug design and discovery
Andre(cid:1) M.deOliveiraandMithun Rudrapal
1 Definitionandconceptofdrugdesignanddiscovery 1
2 Historicalperspectivesofdrugdiscovery 2
3 Process,strategies,andstagesofdrugdiscoveryand
development 4
3.1 Discoveryphase 5
3.2 Preclinicalphase 5
3.3 Clinicalphase 6
3.4 Approvalandpostapprovalphases 7
4 Traditionalandmodernapproachestodrugdiscoveryand
development 7
4.1 Virtualscreening 7
4.2 High-throughputscreening 8
4.3 Phenotypicscreening 8
4.4 Structure-baseddrugdesign 8
4.5 Fragment-baseddrugdesign 8
4.6 Ligand-baseddrugdesign 9
5 Rationaldrugdesign(RDD)andCADD 9
5.1 Structure-baseddrugdesign(SBDD) 10
5.2 Ligand-baseddrugdesign(LBDD) 11
6 Conclusion 12
References 12
2. Fundamental considerations in drug design
ManojKumarMahapatraandMuthukumarKaruppasamy
1 Fundamentalsofrationaldrugdesign(RDD) 17
1.1 Rationaldrugdesign 17
1.2 Structure-baseddrugdesign(SBDD) 18
1.3 Ligand-baseddrugdesign(LBDD) 19
2 Conceptsofphysicochemicalproperties 19
2.1 Structuralpropertiesandstereochemistry 20
2.2 Drugreceptorsandreceptortheories 21
2.3 Pharmacokineticsandpharmacodynamics 22
v
vi Contents
2.4 SARsandQSARs 23
2.5 Prodrugsanddrugmetabolism 23
2.6 Metaboliteantagonismandenzymeinhibition 24
2.7 Nucleicacid-baseddrugdesign 25
2.8 Leadcompounds 25
2.9 Peptidomimeticsandanalogdesign 26
2.10 Reversepharmacologyanddrugrepurposing
strategies 26
3 Fundamentalsofcomputer-aideddrugdesign(CADD) 27
3.1 Structure-baseddrugdesign(SBDD) 28
3.2 Ligand-baseddrugdesign(LBDD) 36
3.3 Virtualscreeningtechniques 39
3.4 ADMEanalysisandmeasuresofdrug-likeness 45
4 Conclusion 47
References 48
3. Ligand-based drug design (LBDD)
VivekYadav,Jurnal Reang, Vinita,andRajivKumar Tonk
1 Introduction 58
2 Randomandnonrandomscreening 58
2.1 Drugmetabolismstudies 59
2.2 Serendipitymethod 59
2.3 Clinicalobservations 60
3 Drugdiscoveryprocess 60
3.1 Ligand-baseddrugdesign(LBDD) 61
3.2 Structure-baseddrugdesign(SBDD) 61
4 Combinatorialchemistry 61
4.1 Unbiasedlibrary 62
4.2 Biasedlibrary 62
5 Leadmodificationsandoptimizationapproaches 63
5.1 Pharmacophore 63
5.2 Structure-activityrelationships(SARs) 63
6 Stereochemistryofdrugmolecules 64
6.1 Importanceindrugaction 65
6.2 Stereoselectivityindrug-receptorinteraction 66
6.3 Stereospecificaspectsindrugdesign 67
6.4 Stereochemistryinbiologicalprocesses 68
6.5 Significanceofstereoselectivity 69
7 Bioisosterism 69
7.1 Needanduseofbioisostericreplacements 70
7.2 Classificationofbioisosterism 71
8 Drugmetabolism 73
8.1 Objectives 74
8.2 Prodrugs 75
8.3 Retrometabolism-baseddrugdesign(RMDD) 80
9 Virtualhigh-throughputscreening(vHTS) 85
Contents vii
9.1 Toolsforvirtualhigh-throughputscreening(vHTS) 85
9.2 Techniquesforvirtualhigh-throughputscreening
(vHTS) 86
9.3 Lipinski’srule 88
9.4 Veberrule 88
9.5 ADMETscreening 89
9.6 Toxicityprediction 90
9.7 Docking-basedvirtualscreening(DBVS) 92
9.8 Pharmacophore-basedvirtualscreening(PBVS) 93
10 Conclusion 97
Acknowledgment 97
References 97
4. Quantitative structure-activity relationships (QSARs)
Andre(cid:1) M.deOliveira
1 QSAR:Fundamentalsandhistoricalbackground 101
1.1 Definition 103
1.2 Historicalbackground 103
2 Hammettequation 103
3 Hansch-Fujitamodel 106
4 FreeandWilsonmethod 107
5 ProtocolsformanagingaQSARstudy 108
6 Conditionsforthevalidityofthemodel 111
6.1 Regardingthevariableselection 111
6.2 Regardingthevariablevalidation 111
6.3 Regardingthemodelvalidation 111
6.4 Regardingtheamountofvariables 114
6.5 Regardingthebiologicalvalidation 114
6.6 Regardingmodelrecycling 114
7 3D-QSAR 115
7.1 CoMFA 115
7.2 CoMSIA 117
7.3 SOMFA 117
7.4 GRID/GOLPE 118
7.5 HASL 118
7.6 COMPASS 118
8 Casestudy 118
9 Conclusion 119
References 121
5. Fundamentals of molecular modeling in drug design
Manish Kumar Tripathi, Shaban Ahmad,RashmiTyagi,
Vandana Dahiya,and ManojKumar Yadav
1 Fundamentalsofcomputationalchemistry 125
2 Basicconceptsofquantummechanics 126
viii Contents
3 Sketchapproach,conversionof2Dstructuresin3Dform,and
generationof3Dcoordinates 128
4 Moleculardynamicssimulationanditscomponents 129
4.1 Forcefields 133
4.2 Geometryoptimization 134
4.3 Energyminimization 135
4.4 Conformationalsearch 135
4.5 Geneticalgorithms 136
4.6 MonteCarlosimulation 137
4.7 Artificialintelligencemethods 138
4.8 Pharmacophoreidentificationandmolecularmodeling 138
5 Molecularrecognitionindrugdesign 140
6 Thermodynamicconsiderationofdrugdesigning 141
6.1 Methodsofthermodynamicmeasurementfor
bimolecularinteractions 142
6.2 Physicalbasisofintermolecularinteraction 143
7 Conclusionandfuturescope 151
References 152
6. Pharmacophore modeling in drug design
SiddharthaMaji,SubratKumarPattanayak,AnikSen,and
Vishnu NayakBadavath
1 Introduction 157
2 Computer-aideddrugdesign 159
3 Pharmacophoreconcept 160
3.1 Ligand-basedpharmacophore 161
3.2 Structure-basedpharmacophore(SBP) 163
4 Pharmacophoremodel-basedvirtualscreening(VS) 164
5 Pharmacophoreelementsandrepresentation 166
6 Generationofpharmacophoremodelsfromreceptor-ligand
complex 168
7 ApplicationsofpharmacophoresinADME-Tox 169
7.1 Pharmacophore-guideddrugtargetidentification 170
7.2 Multitargetsbypharmacophore 170
7.3 Possibleapplicationsofmultitargetligands 171
8 Conclusion 172
References 173
7. Structure-based drug design (SBDD)
Gourav Rakshit, SheikhMurtuja,Banoth KaranKumar,
SankaranarayananMurugesan, and
VenkatesanJayaprakash
1 Computer-aideddrugdesign 181
2 Structure-baseddrugdesign(SBDD) 183
Contents ix
2.1 Overviewoftheprocessesinvolvedinstructure-baseddrug
design(SBDD) 190
2.2 ExamplesofSBDD 190
2.3 CasestudyofSBDD 191
3 Moleculardocking 195
3.1 Variousmodelspertainingtomoleculardocking 196
3.2 Classificationofmoleculardockingsystems 198
3.3 Dockingbasedscreening 198
3.4 Moleculardockingstepsandprocedure/docking
protocol 200
4 Moleculardynamics 209
4.1 ApplicationsofMD 210
4.2 BindingfreeenergycalculationswithMMGBSA/PBSA 212
4.3 MoleculardynamicssimulationusingDESMOND 215
4.4 Casestudy 217
5 Conclusion 222
References 223
8. Recent advances in CADD
TriptiSharma,Sujata Mohapatra,Rasmita Dash,
BiswabhusanRath,andChita Ranjan Sahoo
1 Introduction 232
2 Roleofinformaticsindrugdiscovery 232
2.1 Chemoinformaticsindrugdiscovery 232
3 Databasesusedindrugdiscovery 239
3.1 RecenttrendsofADMET 239
3.2 Predictionofphysicochemicalproperties 240
3.3 PredictionofADMETproperties 242
4 Fragment-baseddrugdesign 244
4.1 LibrarydesignforFBDD 244
4.2 Strategiesinfragment-baseddrugdesign 246
4.3 Generalconsiderationonfragment-baseddrug
design 248
5 Receptor-baseddenovodesign 251
5.1 Methodsinvolvedindenovodrugdesign 251
6 Nucleicacid-baseddrugdesign(NABDD) 253
7 Advancesindrugdesigning 257
7.1 Similaritysearching 257
7.2 Artificialintelligence(AI) 257
7.3 Machinelearning(ML) 258
7.4 Datamining 258
7.5 Networkanalysisandsystembiologytools 258
7.6 Dataanalysistools 259
8 Insilicoapproachesindrugrepurposing 259
8.1 Knowledge-basedapproach 266
8.2 Target/structure-basedapproach 266